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Research ArticleArticle

Analysis and Prediction of Drug Transfer into Human Milk Taking into Consideration Secretion and Reuptake Clearances across the Mammary Epithelia

Hiroki Koshimichi, Kousei Ito, Akihiro Hisaka, Masashi Honma and Hiroshi Suzuki
Drug Metabolism and Disposition December 2011, 39 (12) 2370-2380; DOI: https://doi.org/10.1124/dmd.111.040972
Hiroki Koshimichi
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Kousei Ito
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Akihiro Hisaka
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Masashi Honma
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Hiroshi Suzuki
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Abstract

Medication use during lactation is a matter of concern due to unnecessary exposure of infants to drugs. Although some studies have predicted the extent of drug transfer into milk from physicochemical parameters, drug concentration-time profiles in milk have not been predicted or even analyzed yet. In the present study, a drug transfer model was constructed by defining secretion and reuptake clearances (CLsec and CLre, respectively) between milk and plasma based on unbound drug concentrations. Through the use of this model, drug concentration-time profiles were analyzed in human milk and plasma based on data collected from the literature. CLsec and CLre values were obtained successfully for 49 drugs. Because the CLsec and CLre values were in general similar for each drug, transport across the mammary epithelia was mediated by passive diffusion in most cases. This study demonstrated that the logarithmically transformed values of CLsec and CLre can be predicted from physicochemical parameters with adjusted R2 values of 0.705 and 0.472, respectively. Moreover, 66.7 and 77.8% of predicted CLsec and CLre values were within 3-fold error ranges of the observed values for 45 and 27 drugs, respectively. Finally, time profiles of drug concentrations in milk were simulated from physicochemical parameters. The milk-to-plasma area under the concentration-time curve ratios also were predicted successfully within 3-fold error ranges of the observed values for 71.9% of the drugs analyzed. The method described herein therefore may be useful in predicting drug concentration-time profiles in human milk for newly developed drugs.

Footnotes

  • This work was supported by a research scholarship from the Japan Research Foundation for Clinical Pharmacology; and a Grant-in-Aid for Scientific Research on Innovative Areas HD-Physiology [Grant 22136015] from the Ministry of Education, Science and Culture of Japan.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.040972.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CLsec
    secretion clearance
    CLre
    reuptake clearance
    M/P (AUC)
    milk-to-plasma area under the concentration-time curve ratio
    MW
    molecular weight
    Vm
    milk volume
    Cp(t)
    drug concentration in plasma
    Cm(t)
    drug concentration in milk
    fp
    unbound fraction of drug in plasma
    fm,total
    unbound fraction of drug in milk
    fm,protein
    protein binding in milk
    Papp
    partition coefficient between milk lipid and water
    Tmax
    time of maximum concentration
    log D
    common logarithm of octanol-water distribution coefficient
    log P
    common logarithm of octanol-water partition coefficient
    PSA
    polar surface area
    HBA
    hydrogen bond acceptor
    HBD
    hydrogen bond donor
    BCRP/ABCG2
    breast cancer resistance protein/ATP-binding cassette transporter G2.

  • Received May 31, 2011.
  • Accepted September 21, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (12)
Drug Metabolism and Disposition
Vol. 39, Issue 12
1 Dec 2011
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Research ArticleArticle

PREDICTION OF DRUG TRANSFER INTO HUMAN MILK

Hiroki Koshimichi, Kousei Ito, Akihiro Hisaka, Masashi Honma and Hiroshi Suzuki
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2370-2380; DOI: https://doi.org/10.1124/dmd.111.040972

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Research ArticleArticle

PREDICTION OF DRUG TRANSFER INTO HUMAN MILK

Hiroki Koshimichi, Kousei Ito, Akihiro Hisaka, Masashi Honma and Hiroshi Suzuki
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2370-2380; DOI: https://doi.org/10.1124/dmd.111.040972
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